title: Integrin α6β1 is the main receptor for vascular laminins and plays a role in platelet adhesion, activation, and arterial thrombosis.
abstract: BACKGROUND
  Laminins are major components of basement membranes, well located to interact with platelets upon vascular injury. Laminin-111 (α1β1γ1) is known to support platelet adhesion but is absent from most blood vessels, which contain isoforms with the α2, α4, or α5 chain. Whether vascular laminins support platelet adhesion and activation and the significance of these interactions in hemostasis and thrombosis remain unknown.
  
  
  RESULTS
  Using an in vitro flow assay, we show that laminin-411 (α4β1γ1), laminin-511 (α5β1γ1), and laminin-521 (α5β2γ1), but not laminin-211 (α2β1γ1), allow efficient platelet adhesion and activation across a wide range of arterial wall shear rates. Adhesion was critically dependent on integrin α6β1 and the glycoprotein Ib-IX complex, which binds to plasmatic von Willebrand factor adsorbed on laminins. Glycoprotein VI did not participate in the adhesive process but mediated platelet activation induced by α5-containing laminins. To address the significance of platelet/laminin interactions in vivo, we developed a platelet-specific knockout of integrin α6. Platelets from these mice failed to adhere to laminin-411, laminin-511, and laminin-521 but responded normally to a series of agonists. α6β1-Deficient mice presented a marked decrease in arterial thrombosis in 3 models of injury of the carotid, aorta, and mesenteric arterioles. The tail bleeding time and blood loss remained unaltered, indicating normal hemostasis.
  
  
  CONCLUSIONS
  This study reveals an unsuspected important contribution of laminins to thrombus formation in vivo and suggests that targeting their main receptor, integrin α6β1, could represent an alternative antithrombotic strategy with a potentially low bleeding risk.
authors.affiliation: Unité Mixte de Recherche (UMR) S949, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg, Etablissement Français du Sang (EFS)-Alsace, Strasbourg, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Schaff
authors.forename: ChaoJun
authors.initials: C
authors.lastname: Tang
authors.forename: Eric
authors.initials: E
authors.lastname: Maurer
authors.forename: Catherine
authors.initials: C
authors.lastname: Bourdon
authors.forename: Nicolas
authors.initials: N
authors.lastname: Receveur
authors.forename: Anita
authors.initials: A
authors.lastname: Eckly
authors.forename: Béatrice
authors.initials: B
authors.lastname: Hechler
authors.forename: Christiane
authors.initials: C
authors.lastname: Arnold
authors.forename: Adèle
authors.initials: A
authors.lastname: de Arcangelis
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Cécile V
authors.initials: CV
authors.lastname: Denis
authors.forename: Olivier
authors.initials: O
authors.lastname: Lefebvre
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Georges-Labouesse
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.forename: François
authors.initials: F
authors.lastname: Lanza
authors.forename: Pierre H
authors.initials: PH
authors.lastname: Mangin
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology*; D006801:Humans; D039121:Integrin alpha6beta1 / Q000378:metabolism* / Q000502:physiology; D007797:Laminin / Q000502:physiology; D008638:Mesenteric Arteries / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation / Q000502:physiology*; D010973:Platelet Adhesiveness / Q000502:physiology*; D012307:Risk Factors; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology
chemical_list: D039121:Integrin alpha6beta1; D007797:Laminin